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5 Examining Mechanisms of Breast Cancer Over the Life Course: Implications for Risk
Pages 239-282

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From page 239...
... in early life, as well as mechanistic and animal studies of other environmental exposures, suggest that existing assessments of the role of certain environmental factors derived from studies in adult women, such as those reviewed in Chapter 3, may have been negative or uninformative because they failed to consider critical periods of life stage and exposure -- essentially asking the wrong 239
From page 240...
... The committee sees the need to direct attention to the accumulating evidence that environmental exposures may have a differential impact, depending on their timing during the life course. ENVIRONMENTAL EXPOSURES OVER THE LIFE COURSE AS DETERMINANTS OF BREAST CANCER RISK The female breast is not static; it changes in structure and function over the life course.
From page 241...
... . Preconceptional parental exposure to ionizing radiation was not associated with an increased risk of childhood leukemia (Wakeford, 1995)
From page 242...
... , the number of mammary stem cells is determined during in utero or immediate postnatal life and is under the influence of estrogens and components of the insulin-like growth factor system during pregnancy. They hold that the number of mammary tissue-specific stem cells is the core determinant of breast cancer risk.
From page 243...
... breast cancer risk if prenatal exposure to them promotes the formation of greater numbers of breast stem cells. There is growing evidence from rodent models to indicate that exposure to xenoestrogens during the prenatal and neonatal periods may affect mammary gland development and alter risk for cancer later in life (Soto et al., 2008)
From page 244...
... . In utero DES exposure is theorized to increase mammary cancer susceptibility by slowing mammary gland maturation and development (Jenkins et al., 2011)
From page 245...
... . During this period, however, the body is preparing for puberty and the next stage of mammary gland development.
From page 246...
... . Further investigation is needed to understand the relation between activity levels in childhood and the timing of puberty or other factors that may influence breast cancer risk in later life.
From page 247...
... . Differences in the impact of pre- and postnatal exposures in these animal models highlight the potential for the timing of human exposure to genistein, and likely other xenoestrogens, to have differing impacts on breast cancer risk.
From page 248...
... . Early age at menarche is an established risk factor for breast cancer (Kelsey and Bernstein, 1996)
From page 249...
... . The contribution of timing of puberty and onset of menarche to increased breast cancer risk may be related to estrogen receptor signaling or to other mechanisms discussed later in this chapter.
From page 250...
... The neutral or inverse association between weight or BMI and breast cancer during the reproductive period differs from the increased risk found during the years following menopause. Smoking, hormone therapy, and radiation are examples of other risk factors that may have differential effects over the life course and across the reproductive period.
From page 251...
... . This type of process may explain the association in humans between young age at first pregnancy and reduced breast cancer risk, and the increased risk associated with nulliparity and late age at first pregnancy.
From page 252...
... , supporting the influence of hormonal factors during pregnancy and its period of rapid breast proliferation. Other evidence that pregnancy can modify breast cancer risk comes from the literature on smoking and breast cancer.
From page 253...
... Clear evidence from studies of menopausal hormone therapy also shows that breast cancer risks can be influenced by exposures during this life stage. Postmenopausal use of hormonal therapy that combines estrogen and progestin increases both the incidence of and mortality from breast
From page 254...
... . Among estrogen-only users, there was no association with breast cancer risk if use was initiated 5 or more years after menopause (RR = 1.05, 95% CI, 0.90–1.24)
From page 255...
... , can include pathophysiological conditions, such as obesity. Accumulated damage from both internal and external carcinogenic events or risk factors drives cancer development through multiple stages from normal cells through preneoplasia to metastatic disease, with many of these stages recognizable as distinct entities in the process of tumor development at the cellular (e.g., lobular hyperplasia)
From page 256...
... . Nuclear Hormone Receptor Signaling The steroid hormones, which include estrogens and progestogens, are involved in the development and maintenance of female reproductive characteristics, via their physiological effects on a broad range of tissues (Björnström and Sjöberg, 2005)
From page 257...
... The receptors for the steroid hormones are part of a larger family of nuclear hormone receptors (Aranda and Pascual, 2001)
From page 258...
... Relatively little is known about how the effects of other mitogens are modulated during the life course to increase or decrease their carcinogenic potential. Some existing data suggest that promotion of growth by mitogens early in life may modulate breast cancer risk later in life.
From page 259...
... The nongenomic effects of steroid hormones involve a subpopulation of classical receptors that associate with sig naling complexes in either the cytoplasm or the plasma cell membrane (Weinberg, 2007)
From page 260...
... . Studies in animal models have demonstrated that perinatal exposure to xenoestrogens can reprogram the development of the mammary gland and reproductive tract, causing alterations in tissue morphology and gene expression (Muñoz-de-Toro et al., 2005; Durando et al., 2007; Murray et al., 2007; Vandenberg et al., 2008; Rudel et al., 2011)
From page 261...
... Environmental exposures may modulate the effectiveness of the immune system in detecting or eliminating cancer cells. For example, the environmental estrogen genistein, present at levels associated with soy consumption, has been shown in studies using human breast cancer cell lines grown in mice to block the ability of cytotoxic T-cells and natural killer cells to recognize and destroy breast cancer cells during immunosurveillance (Jiang et al., 2008)
From page 262...
... . More needs to be learned about how environmental factors influence immunoediting and how modulation of immune function by environmental exposures over the life course influences breast cancer risk.
From page 263...
... Alternatively, exposure to a carcinogen may disrupt the interactions between a cell and its external environment in a manner that permits transformation. Ionizing radiation has carcinogenic potential in both the breast and the rodent mammary gland, and it has been demonstrated to elicit rapid remodeling of the mammary gland ECM (Barcellos-Hoff, 1993)
From page 264...
... . Further research is required to elucidate the mechanisms underlying the association between mammographic density and breast cancer risk, including the influence of environmental factors in altering breast tissue composition.
From page 265...
... Obesity probably affects breast cancer risk through several different and overlapping pathways (Fletcher et al., 2005; Slattery et al., 2007; WCRF/AICR, 2007; Cleary and Grossmann, 2009)
From page 266...
... . Studies have produced conflicting results regarding the association between higher IGF-1 levels and increased breast cancer risk (Yu and Rohan, 2000; Renehan et al., 2004; Shi et al., 2004; Sugumar et al., 2004; Fletcher et al., 2005)
From page 267...
... . ATH also plays a role in increased insulin resistance and chronic inflammation, potentially leading to an increased cancer risk (Roberts et al., 2010)
From page 268...
... Although studies that take into account the timing of exposure will be challenging to conduct, the committee strongly recommends that both epidemiologic and laboratory investigations of breast cancer risk factors specify the stage of the life course being studied (see Chapter 7)
From page 269...
... 2011. Breast cancer risk in relation to the interval between menopause and starting hormone therapy.
From page 270...
... 2002. Reproductive factors and breast cancer risk.
From page 271...
... , IGF binding protein 3 (IGFBP3) , and breast cancer risk: Pooled individual data analysis of 17 prospective studies.
From page 272...
... 1998. Menstrual cycle characteristics and history of ovula tory infertility in relation to breast cancer risk in a large cohort of U.S.
From page 273...
... 2010. Amphiregulin mediates estrogen, progesterone, and EGFR signaling in the normal rat mammary gland and in hormone-dependent rat mammary cancers.
From page 274...
... Breast Cancer Res 12(6)
From page 275...
... Potential mechanisms of breast cancer risk associated with mammographic density: Hypotheses based on epidemiological evidence. Breast Cancer Res 10(1)
From page 276...
... 1993. Estrogen and progesterone regulate secretion of insulin-like growth factor binding proteins by human breast cancer cells.
From page 277...
... -I, IGF binding protein-3, and cancer risk: Systematic review and meta-regression analysis. Lancet 363(9418)
From page 278...
... 2001. Mammary gland architecture as a determining factor in the susceptibility of the human breast to cancer.
From page 279...
... 1990. Role of insulin-like growth factors and the type I insulin-like growth factor receptor in the estrogen-stimulated pro liferation of human breast cancer cells.
From page 280...
... 2008. The role of early life genistein exposures in modifying breast cancer risk.
From page 281...
... Breast Cancer Res Treat 123(1)


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